Structure-guided discovery of quinazoline derivatives as potent FtsZ inhibitors in combating bacterial infections

The scarcity of novel antibiotics effective against bacterial infections, coupled with the escalating threat of antibiotic resistance, represents one of the most pressing challenges in global public health and agriculture. While filamenting temperature-sensitive mutant Z (FtsZ) has emerged as a promising therapeutic target in antibacterial drug development, there remains a pressing need for both structural diversification and mechanistic exploration to advance next-generation FtsZ-targeting antimicrobial agents.

44 of quinazoline derivatives was devised for thorough investigation into their structure-activity relationships and the FtsZ-targeting behavior.

The antimicrobial efficacy was evaluated using turbidimetric assays and pot experiments. Additional characterization, such as isothermal titration calorimetry (ITC), GTPase inhibition assay, circular dichroism, were employed to validate the antibacterial mechanism of D4. Transmission electron microscopy and fluorescence microscopy were used to verify changes in bacterial morphology. Finally, drug-likeness studies were performed using acute toxicity tests on earthworms, along with pesticide-like analyses, and ADMET property studies.

Compound D4 demonstrated broad-spectrum bactericidal activity (EC₅₀ values ranging from 1.57 μg mL^-1 to 6.18 μg mL^-1 against various pathogenic bacteria) and significant efficacy (44.05%-50.30%) in controlling rice bacterial leaf blight, along with favorable drug-like properties. The ITC results indicated that a dissociation constant (K_d) of D4 to XooFtsZ was 3.82 μM and formed nearly a 1:2 binding for the XooFtsZ-D4 complex. Fluorescence titration analysis also demonstrated that compound D4 has a good binding ability with the XooFtsZ protein. And GTPase inhibition result given the 107.90 μM IC₅₀ value for D4. Comprehensive bioassays indicated that D4 interacted within or near the PC190723 binding pocket of XooFtsZ, thereby inhibiting its GTPase activity, inducing protein aggregation, and modulating division-related genes, ultimately leading to bacterial cell death.

In short, these experimental findings suggest that the quinazoline-based compound D4 may serve as a potential FtsZ inhibitor for addressing bacterial infections.